Submitted by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2015-01-07T12:52:36Z No. of bitstreams: 2 livia_mara_fontes_costa_torres.pdf: 2305808 bytes, checksum: 7f9c5a4633cd450fb0283a8996d7fa96 (MD5) license_rdf: 23898 bytes, checksum: e363e809996cf46ada20da1accfcd9c7 (MD5) / Approved for entry into archive by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2015-01-07T12:53:08Z (GMT) No. of bitstreams: 2 livia_mara_fontes_costa_torres.pdf: 2305808 bytes, checksum: 7f9c5a4633cd450fb0283a8996d7fa96 (MD5) license_rdf: 23898 bytes, checksum: e363e809996cf46ada20da1accfcd9c7 (MD5) / Approved for entry into archive by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2015-01-07T12:53:01Z (GMT) No. of bitstreams: 2 livia_mara_fontes_costa_torres.pdf: 2305808 bytes, checksum: 7f9c5a4633cd450fb0283a8996d7fa96 (MD5) license_rdf: 23898 bytes, checksum: e363e809996cf46ada20da1accfcd9c7 (MD5) / Approved for entry into archive by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2015-01-07T12:54:15Z (GMT) No. of bitstreams: 2 livia_mara_fontes_costa_torres.pdf: 2305808 bytes, checksum: 7f9c5a4633cd450fb0283a8996d7fa96 (MD5) license_rdf: 23898 bytes, checksum: e363e809996cf46ada20da1accfcd9c7 (MD5) / Made available in DSpace on 2015-01-07T12:54:15Z (GMT). No. of bitstreams: 2 livia_mara_fontes_costa_torres.pdf: 2305808 bytes, checksum: 7f9c5a4633cd450fb0283a8996d7fa96 (MD5) license_rdf: 23898 bytes, checksum: e363e809996cf46ada20da1accfcd9c7 (MD5) Previous issue date: 2014 / Sistemas de libera??o modificada de f?rmacos possibilitam controlar a taxa de libera??o das subst?ncias ativas e direcion?-las aos seus locais de a??o evitando outras regi?es onde o f?rmaco exerce toxicidade, dessa forma ? poss?vel reduzir a ocorr?ncia de efeitos adversos, o que aumenta a aceitabilidade do tratamento pelo paciente, al?m de torn?-lo mais eficaz. Com o prop?sito de verificar a possibilidade de utiliza??o do sistema polim?rico PHB/PCL (poli(3-hidroxibutirato) / poli(??caprolactona)) em sistemas de libera??o controlada, o presente trabalho tem como objetivo preparar filmes polim?ricos e microesferas a partir de blendas PHB/PCL compatibilizadas com o copol?mero P(HB-co-CL), e caracterizar esses materiais, uma vez que os perfis de libera??o associam-se a propriedades f?sico-qu?micas inerentes aos materiais que o constituem, atrav?s de t?cnicas de an?lise t?rmica, difra??o de raios-x e microscopia eletr?nica de varredura. Com a realiza??o deste trabalho foi poss?vel verificar que a adi??o do compatibilizante em blendas PHB/PCL(20/80) e PHB/PCL(80/20) ? capaz de aumentar a intera??o entre os componentes polim?ricos dos sistemas, favorecendo a obten??o de materiais com propriedades intermedi?rias ?s apresentadas pelos homopol?meros. Al?m disso, verificou-se que o elevado grau de cristalinidade apresentado por determinados materiais polim?ricos, que dificulta sua aplica??o em sistemas de libera??o de f?rmacos, pode ser alterado por meio de uma simples mistura f?sica entre diferentes pol?meros. Tanto atrav?s da associa??o dos pol?meros PHB e PCL na forma de blendas quanto pela compatibiliza??o desses materiais com a adi??o do copol?mero ? formula??o foi poss?vel modificar o perfil de cristalinidade apresentando por esses sistemas polim?ricos. Verificou-se que o PCL associado ao copol?mero apresentou perfil cristalino muito semelhante ao PCL puro, mas o mesmo evento n?o foi observado para o PHB compatibilizado, que apresentou menor cristalinidade se comparado ao homopol?mero. Em rela??o ?s blendas PHB/PCL(20/80) e PHB/PCL(80/20) observou-se menor cristalinidade para estes sistemas se comparados aos homopol?meros puros, no entanto a presen?a do copol?mero em ambas as blendas modifica a cristalinidade aumentando a intensidade de picos cristalinos. Essa altera??o de cristalinidade ? capaz de influenciar a degrada??o da matriz polim?rica, propriedade que pode ter aplicabilidade na modula??o da libera??o de ativos em sistemas de libera??o controlada. Estes sistemas podem ser desenvolvidos mediante a formula??o de microesferas polim?ricas e incorpora??o de ativos em sua matriz. Neste trabalho, pela primeira vez, foi poss?vel obter microesferas a partir de blendas PHB/PCL(80/20) e PHB/PCL(80/20) compatibilizada com o copol?mero P(HB-co-CL), que devido ?s propriedades de biocompatibilidade e biodegradabilidade apresentadas pelos materiais constituintes, representam sistemas promissores para aplica??o em sistemas de libera??o controlada de f?rmacos. / ABSTRACT Modified drug delivery systems allow to control the release rate of active substances and direct them to their action sites avoiding other regions where the drug produces toxic effects, so it is possible to reduce the occurrence of side effects, which increases the acceptability of treatment by the patient, and make it more effective. In order to verify the possibility to use the polymer system PHB/PCL (poly(3- hydroxybutyrate) / poly (?-caprolactone)) in controlled release systems, the present work aims to prepare polymeric films and microspheres from blends PHB/PCL compatibilized with the copolymer P(HB-co-CL) and characterize these materials, as the release profiles are associated with physico-chemical materials properties, using thermal analysis, x-ray diffraction spectroscopy and scanning electron microscopy. With this work we found that the addition of compatibilizer in blends PHB/PCL(20/80) and PHB/PCL(80/20) is able to increase the interaction between the polymer components of the systems, favoring to obtain materials with properties intermediate to those presented by homopolymers. Furthermore, it was found that the crystallinity degree presented by certain polymeric materials, which makes difficult their application in drug delivery systems, can be changed by a simple physical blend of different polymers. By combining both PHB and PCL polymers as compatibilizing blends of these materials by the copolymer addition to the formulation, was possible to modify the crystallinity profile present in these polymeric systems. It was found that PCL associated with the copolymer showed crystalline profile very similar to pure PCL, but the same event was not observed for the compatibilized PHB , which had lower crystallinity compared to homopolymer. Regarding blends PHB/PCL(20/80) and PHB/PCL(80/20) was observed lower crystallinity for these systems compared to pure homopolymer, however the copolymer presence in the blends modifies both systems increasing crystallinity intensity of crystalline peaks. This change of crystallinity can influence the polymer matrix degradation, a property that may have applicability in modulating the release of drugs in controlled release systems. These systems can be obtained through the development of polymeric microspheres and incorporation of drugs in its matrix. In this work, for the first time , it was possible to obtain microspheres from blends of PHB/PCL(80/20) and PHB/PCL(80/20) associated with the copolymer P(HB-co-CL), which due to the properties of biocompatibility and biodegradability presented by the constituent materials represent promising systems for application in controlled drug release systems. / Disserta??o (Mestrado) ? Programa de P?s-gradua??o em Ci?ncias Farmac?uticas, Universidade Federal dos Vales do Jequitinhonha e Mucuri, 2013.

Submitted by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2016-01-06T17:12:21Z No. of bitstreams: 2 francisca_gabriela_lopes_rosado.pdf: 2418582 bytes, checksum: 1085042d57771e6ef9b3cf3240ae88ab (MD5) license_rdf: 22974 bytes, checksum: 99c771d9f0b9c46790009b9874d49253 (MD5) / Approved for entry into archive by Rodrigo Martins Cruz (rodrigo.cruz@ufvjm.edu.br) on 2016-01-07T12:01:32Z (GMT) No. of bitstreams: 2 license_rdf: 22974 bytes, checksum: 99c771d9f0b9c46790009b9874d49253 (MD5) francisca_gabriela_lopes_rosado.pdf: 2418582 bytes, checksum: 1085042d57771e6ef9b3cf3240ae88ab (MD5) / Made available in DSpace on 2016-01-07T12:01:33Z (GMT). No. of bitstreams: 2 license_rdf: 22974 bytes, checksum: 99c771d9f0b9c46790009b9874d49253 (MD5) francisca_gabriela_lopes_rosado.pdf: 2418582 bytes, checksum: 1085042d57771e6ef9b3cf3240ae88ab (MD5) Previous issue date: 2014 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (Capes) / Funda??o de Amparo ? Pesquisa do estado de Minas Gerais (FAPEMIG) / A oxida??o de efluentes sint?ticos contendo os f?rmacos paracetamol (PCT) e dipirona (DPN), ambos analg?sicos largamente utilizados por humanos e animais foi conduzida pelos processos O3, O3/UV, H2O2/UV e H2O2/UV/O3 via rea??o direta (oz?nio molecular), indireta (radical hidroxila) e mista (O3/HO?) manipulando-se o pH do meio reacional. Essas subst?ncias tem grande resist?ncia aos processos convencionais de tratamento de efluentes e, assim buscam-se ferramentas mais eficientes para a degrada??o desses f?rmacos. A remo??o dos f?rmacos PCT e DPN nas amostras tratadas com os diferentes POA foi monitorada utilizando a t?cnica cromatografia l?quida de alta efici?ncia (HPLC). A quantidade total de compostos arom?ticos e o grau de mineraliza??o da mat?ria org?nica dissolvida foram avaliados por meio dos par?metros UV (254 nm), Demanda Qu?mica de Oxig?nio (DQO) e de Carbono Org?nico Total (COT). Al?m disso, a susceptibilidade a biodegradabilidade foi avaliada por meio da raz?o da DQO/COT. Os resultados experimentais mostraram que o tempo gasto para a degrada??o depende da natureza do f?rmaco, bem como do pH e do tipo de processo oxidativo. Verificou-se uma elevada percentagem de remo??o (95%) e um percentual moderado de mineraliza??o (35%) para os estudos utilizando os processos O3 (pH 12) e O3/UV. De um modo geral, verificou-se um aumento da biodegradabilidade das amostras tratadas para os diferentes tratamentos oxidativos. No caso dos processos H2O2/UV e H2O2/UV/O3 a remo??o dos f?rmacos foi alta, especialmente no caso do processo H2O2/ UV/O3 onde ap?s 45 min e dose de 200 ppm de per?xido obteve-se ?88% de remo??o dos f?rmacos. No caso do processo H2O2(800ppm)/O3/UV e para o f?rmaco PCT, verificou-se percentagens de remo??o de DQO e COT de 77% e 42%, respectivamente. J? para o f?rmaco DPN, os valores correspondentes obtidos foram de 70% e 68%, respectivamente. Analisando os resultados observou-se que a remo??o da DQO e do COT foi maior para os processos processo H2O2/UV/O3. Por outro lado, a maior remo??o das subst?ncias parentais (PCT e DPN) foi obtida utilizando o processo O3 (pH 12). A partir dos valores das constantes de velocidade em fun??o do pH estimou-se a contribui??o dos processos de oxida??o por via direta e indireta. De um modo geral, o estudo revelou que o uso dos presentes POA e/ou ozoniza??o pode constituir um processo de tratamento alternativo vi?vel para a remo??o/degrada??o dos f?rmacos PCT e DPN presente em ?guas contaminadas. / Disserta??o (Mestrado) ? Programa de P?s-Gradua??o em Qu?mica, Universidade Federal dos Vales do Jequitinhonha e Mucuri, 2014. / ABSTRACT The oxidation of synthetic wastewaters containing the drugs Acetaminophen (PCT) and Dipyrone (DPN), which are analgesics of widespread use by the human being and animals, was carried out by means of the O3, O3/UV, H2O2/UV e H2O2/UV/O3 oxidative processes. The ?direct? oxidation process was promoted by action of the O3 (acidic solutions) while in the case of the ?indirect? processes the application of the Advanced Oxidation Processes (AOPs) has permitted the use of the hydroxyl radical (HO?) as the major oxidant. These substances are recalcitrant towards the conventional wastewater treatments and, therefore, the search for an efficient treatment for these effluents is of current interest. The removal of PCT and DPN in the treated samples using the different AOPs was monitored using the high performance liquid chromatography (HPLC) technique. The total amount of aromatics and the degree of mineralization of the dissolved organic matter were evaluated by means of the UV(254 nm) technique and the Chemical Oxygen Demand (COD) and Total Organic Carbon (COT) methods, respectively. In addition, biodegradability susceptibility was evaluated by means of the COD/TOC ratio. The experimental findings showed that the time spent for degradation depends on the nature of the drug, as well as on the pH and the type of the oxidative process. It was verified for the studies using the O3(pH 12) and O3/UV processes a high percentage of removal (95%) and a moderate percentage of mineralization (35%). On the whole, it was verified an increase in the biodegradability of the treated samples for the different oxidative treatments. In the case of the H2O2/UV and H2O2/UV/O3 processes the removal of PCT and DPN was high, especially in the case of the H2O2/UV/O3 where after 45 min and by using a peroxide dosage of 200 ppm a percentage of removal of ?88% was obtained. In the case of the H2O2(800ppm)/UV/O3 process and for PCT, it was verified percentages of removal for COD and COT of 77% and 42%, respectively. Accordingly, the corresponding values obtained for DPN were 70% and 68%, respectively. As a rule, the removal of COD and COT was higher for the H2O2/UV/O3 process. On the contrary, a higher removal (e.g., HPLC) of the parental substances (PCT and DPN) was obtained using the O3 (pH 12) process. In the case of the ozonation the contribution of the direct and indirect oxidation processes was evaluated from the values of the pseudo first-order rate constants obtained in the acidic and alkaline conditions. On the whole, the current study has revealed that the use of the present AOPs and/or ozonation can constitute a viable alternative treatment process for the removal/degradation of the PCT and DPN drugs present in contaminated waters.

Submitted by Caroline Xavier (caroline.xavier@pucrs.br) on 2017-06-23T14:56:57Z No. of bitstreams: 1 DIS_FERNANDA_TEIXEIRA_SUBTIL_COMPLETO.pdf: 1495988 bytes, checksum: 70f1cb1dccabfa7c302effb51db76e03 (MD5) / Made available in DSpace on 2017-06-23T14:56:57Z (GMT). No. of bitstreams: 1 DIS_FERNANDA_TEIXEIRA_SUBTIL_COMPLETO.pdf: 1495988 bytes, checksum: 70f1cb1dccabfa7c302effb51db76e03 (MD5) Previous issue date: 2017-03-03 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / The high incidence of tuberculosis is a great concern worldwide. Different strategies are being developed by the World Health Organization to fight tuberculosis. Amongst the three pillars that are part of the End TB Strategy, we can highlight the intensive research and innovation pillar. In this extent, the development of new drugs for tuberculosis treatment is a field that is gaining importance. The 2(quinolin-4-yloxy) acetamides are molecules that showed promising bactericidal effects in Mycobacterium tuberculosis, which motivated us to continue studying to improve their mycobactericidal activity and also perform their chemical and biological characterization. In order to continue the 2(quinolin-4-yloxy) acetamides derivatives development, the target identification of these molecules is a keystone and is also the focus of this study. Initially, it was hypothesized that DNA gyrase was their molecular target due to the great chemical similarities between the 2(quinolin-4-yloxy) acetamides and the fluoroquinolones. Despite our results that the 2(quinolin-4-yloxy) acetamides have diminished effects in ofloxacin resistant clinical isolates, the results obtained with the gyrA point mutant and with DNA gyrase protein revealed that this enzyme is not the molecular target of these compounds. The new target identification strategy involved the selection of spontaneous mutants for our lead compound 12L, characterization of this mutant strain against other 2(quinolin-4-yloxy) acetamides derivates and whole genome sequencing. Whole genome sequencing data allowed the identification of a single mutation (T313A) in the QcrB protein, which is the B subunit of cytochrome bc1 complex. This mutation was confirmed by Sanger sequencing and molecular docking results confirmed the importance of this residue for proteindrug interaction. The cytochrome bc1 complex is involved in the electron transport of the bacilli?s respiratory chain, and therefore it appears to be an interesting target, especially to treat the latent form of the disease. We hope that this work contributes to the 2(quinolin-4-yloxy) acetamides development for tuberculosis treatment. / A alta incid?ncia da tuberculose, em ?mbito mundial, ? de grande preocupa??o. Para combater esta doen?a, diferentes estrat?gias v?m sendo desenvolvidas pela Organiza??o Mundial da Sa?de (OMS). Dentre os pilares que comp?em a End TB strategy, podemos destacar a pesquisa intensiva e a inova??o. Neste ?mbito, o desenvolvimento de novos f?rmacos para tuberculose vem ganhando destaque. As 2(quinolin-4-il?xi) acetamidas s?o mol?culas que demonstraram resultados bactericidas promissores frente ao Mycobacterium tuberculosis, o que nos motivou a realizar novos estudos para melhorar a atividade e realizar a caracteriza??o qu?mica e biol?gica destas mol?culas. A fim de continuar o desenvolvimento da s?rie quinol?nica, a identifica??o do seu alvo molecular foi o foco deste trabalho. Inicialmente, levantou-se a hip?tese de que a DNA girase seria o alvo molecular, uma vez que as 2(quinolin- 5-il?xi) acetamidas possuem grande similaridade estrutural com as fluoroquinolonas. Apesar das 2(quinolin-4-il?xi) acetamidas terem apresentado menor atividade frente a isolados cl?nicos resistentes a ofloxacino, os resultados de atividade obtidos frente a uma mutante pontual de gyrA e frente ? prote?na indicam que a DNA girase n?o ? o alvo destas mol?culas. A nova estrat?gia para identifica??o de alvo envolveu a sele??o de mutantes espont?neos para o composto l?der 12L, caracteriza??o desta cepa frente aos demais compostos da s?rie e sequencimento total do genoma. Este permitiu a identifica??o de uma ?nica muta??o (T313A) localizada na prote?na QcrB, que ? a subunidade B do complexo citocromo bc1. Esta muta??o foi confirmada por sequenciamento de Sanger e o docking molecular aferiu a import?ncia deste res?duo na intera??o prote?na-composto. O complexo citocromo bc1 est? envolvido no transporte de el?trons na cadeia respirat?ria do bacilo, e por isso ? um alvo molecular interessante, principalmente para combater a forma latente da doen?a. Esperamos que este trabalho contribua no processo de desenvolvimento das 2(quinolin-4-il?xi) acetamidas para o tratamento da tuberculose.

Submitted by Caroline Xavier (caroline.xavier@pucrs.br) on 2017-09-22T17:48:51Z No. of bitstreams: 1 TES_RODRIGO_SCOPEL_COMPLETO.pdf: 15566888 bytes, checksum: 14d33da014482ed0a63266b36e2baee6 (MD5) / Approved for entry into archive by Caroline Xavier (caroline.xavier@pucrs.br) on 2017-09-22T17:49:44Z (GMT) No. of bitstreams: 1 TES_RODRIGO_SCOPEL_COMPLETO.pdf: 15566888 bytes, checksum: 14d33da014482ed0a63266b36e2baee6 (MD5) / Made available in DSpace on 2017-09-22T17:49:54Z (GMT). No. of bitstreams: 1 TES_RODRIGO_SCOPEL_COMPLETO.pdf: 15566888 bytes, checksum: 14d33da014482ed0a63266b36e2baee6 (MD5) Previous issue date: 2017-03-29 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Human skin is an attractive option for applying active compounds that minimize adverse effects due to low systemic exposure when compared with other routes of administration. These compounds can permeate the skin layer by the intercellular, intracellular and follicular routes resulting in a topical and/or transdermal delivery. The delivery of active compounds via nanotechnology-based systems may revolutionize the treatment of several disorders including the ones related with the skin. Among these systems, liposomes, and biocompatible and bioabsorbable polymeric nanoparticles, are the technologies with the greatest growth in the field. Therefore, it is ideal to look for mechanisms that couple the mechanical advantages of polymeric nanoparticles with the biomimetic characteristics of liposomes. The aim of this work is to study the synthesis and behavior of hybrid nanoparticles comprising a polymeric core (PLGA) coated by a mixture of lipids (HSPC:CHOL:DSPE-PEG) functionalized to ligand molecules. Initially, it is proposed the conjugation of vitamin D on the surface of the hybrid nanoparticles to target them for specific receptors (VDR) present on melanocytes and melanoma cells. Subsequently, the synthesis of a RGD peptide is carried out aiming to verify the possibility of applying the same methodology for targeting more specific receptors of these cells. Seeking a greater understanding about how the drug is released from these nanoparticles, in vitro experiments of drug release are conducted. In addition, an explicit analytical solution of the mathematical model proposed by Baker-Lonsdale is proposed in order to obtain information regarding the transport phenomena that controls the drug release. Finally, it is proposed a skin permeation mathematical model with boundary conditions adapted for the target nanoparticles. / A pele ? uma rota de entrega atrativa para a aplica??o de f?rmacos que minimiza efeitos adversos devido ? baixa exposi??o sist?mica quando comparada a outras vias de aplica??o. Estes compostos podem permear a camada pelas rotas intercelular, intracelular e transap?ndice resultando em uma entrega t?pica e/ou transd?rmica. A entrega de compostos atrav?s de sistemas baseados na nanotecnologia pode revolucionar o tratamento de diversas doen?as e disfun??es onde, entre estes sistemas de libera??o, lipossomas e nanopart?culas polim?ricas biocompat?veis, s?o as tecnologias que apresentam maior crescimento. A partir disso, torna-se ideal a pesquisa de mecanismos que contemplem as vantagens mec?nicas das nanopart?culas polim?ricas com as caracter?sticas biomim?ticas dos lipossomas. O objetivo deste trabalho ? estudar a s?ntese e comportamento frente ? aplica??o t?pica de nanopart?culas h?bridas compostas por um n?cleo de PLGA e revestidas com uma mistura de fosfolip?dios (HSPC:COL:DSPE-PEG) funcionalizada com mol?culas ligantes. Inicialmente, prop?e-se a conjuga??o de vitamina D na superf?cie das nanopart?culas h?bridas com o objetivo de direcionar as mesmas para receptores espec?ficos de vitamina D (VDR) presentes em melan?citos e c?lulas de melanoma. Em sequ?ncia, a s?ntese do pept?deo RGD ? realizada verificando a aplicabilidade da metodologia para um futuro direcionamento a receptores mais espec?ficos presentes nestas c?lulas. Visando um maior entendimento sobre o comportamento de libera??o de f?rmacos a partir destas nanopart?culas, testes in vitro de libera??o s?o conduzidos. Al?m disso, ? sugerida uma solu??o anal?tica expl?cita do modelo matem?tico de libera??o proposto por Baker-Lonsdale com o objetivo de obter informa??es referentes ao fen?meno de transporte controlador do processo de libera??o de f?rmacos. Por fim, prop?e-se um modelo matem?tico de permea??o cut?nea com condi??es de contorno adequadas para estes nanocarreadores.

Submitted by PPG Biologia Celular e Molecular (bcm@pucrs.br) on 2018-01-16T11:14:58Z No. of bitstreams: 1 FERNANDA_SOUZA_MACCHI_DIS.pdf: 4481387 bytes, checksum: 59f26900156a5b5c1a267893bdc6f655 (MD5) / Approved for entry into archive by Caroline Xavier (caroline.xavier@pucrs.br) on 2018-01-26T12:32:00Z (GMT) No. of bitstreams: 1 FERNANDA_SOUZA_MACCHI_DIS.pdf: 4481387 bytes, checksum: 59f26900156a5b5c1a267893bdc6f655 (MD5) / Made available in DSpace on 2018-01-26T12:40:54Z (GMT). No. of bitstreams: 1 FERNANDA_SOUZA_MACCHI_DIS.pdf: 4481387 bytes, checksum: 59f26900156a5b5c1a267893bdc6f655 (MD5) Previous issue date: 2017-11-22 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Using the classical hybridization approach series of 1H-benzo[d]imidazoles and 3,4-dihydroquinazolin-4-ones were synthesized and evaluated as inhibitors of Mycobacterium tuberculosis growth. Chemical modifications and structure-activity relationship studies yielding potent antitubercular agents with minimum inhibitory concentration values in submicromolar range. Further, the synthesized compounds were active against drug-resistant strains and were devoid of apparent toxicity to HepG2, HaCat, and Vero cells. In addition, some 3,4-dihydroquinazolin-4-ones showed low risk of cardiac toxicity, no signals of neurotoxicity or morphological alteration in zebrafish (Danio rerio) models. Therefore, these data denote that this class of molecules may furnish candidates for future development of novel anti-TB drug alternatives. / Usando a abordagem cl?ssica de hibrida??o molecular, s?ries de 1H-benzo[d]imidaz?is e 3,4-diidroquinazolin-4-onas foram sintetizadas e ensaiadas como inibidores de crescimento de Mycobacterium tuberculosis. Modifica??es qu?micas e estudos de rela??o estrutura-atividade nos conduziram a potentes agentes antituberculose com valores submicromolares de concentra??o inibit?ria m?nima. Os compostos sintetizados tamb?m foram ativos contra cepas resistentes ? f?rmacos e demonstraram desprovida citotoxicidade aparente em c?lulas HepG2, HaCat e Vero. Al?m disso, algumas 3,4-diidroquinazolin-4-onas apresentaram baixo risco de toxicidade card?aca, e nenhum sinal de neurotoxicidade ou altera??o morfol?gica em modelo de peixe-zebra (Danio rerio). Sendo assim, os resultados indicam que essa classe de mol?cular pode fornecer condidatos para o desenvolvimento futuro de novos f?rmacos contra a tuberculose.

Submitted by PPG Medicina e Ci?ncias da Sa?de (medicina-pg@pucrs.br) on 2018-03-16T19:55:06Z No. of bitstreams: 1 THA?S_CRISTINA_MURAD?S_DIS.pdf: 883340 bytes, checksum: 6481cc56bc005f400fcfc1ae75cea11e (MD5) / Approved for entry into archive by Tatiana Lopes (tatiana.lopes@pucrs.br) on 2018-03-28T13:57:53Z (GMT) No. of bitstreams: 1 THA?S_CRISTINA_MURAD?S_DIS.pdf: 883340 bytes, checksum: 6481cc56bc005f400fcfc1ae75cea11e (MD5) / Made available in DSpace on 2018-03-28T14:01:44Z (GMT). No. of bitstreams: 1 THA?S_CRISTINA_MURAD?S_DIS.pdf: 883340 bytes, checksum: 6481cc56bc005f400fcfc1ae75cea11e (MD5) Previous issue date: 2017-12-19 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / New effective compounds for tuberculosis (TB) treatment are currently needed. This study analyzed the anti-TB activity of a series of 16 quinoxaline-derived chalcones. From an initial in vitro screening, six molecules, namely N5, N9, N10, N15, N16, and N23 inhibited the growth of the M. tuberculosis H37Rv laboratory strain. The three compounds (N9, N15 and N23) with the lowest MIC values (3.13, 6.25, 5 ?g/mL, respectively) were further tested against clinical isolates and laboratory strains harboring mutations in katG or inhA genes. From these experimental set, N9 was selected as the lead compound for further investigations. This chalcone displayed a synergistic effect when combined with moxifloxacin, according to assessment in a checkerboard assay. Noteworthy, the anti-TB effects of N9 did not rely on inhibition of mycolic acids or non-hydroxylated fatty acids synthesis, circumventing important mechanisms of resistance in mycobacteria. Considering the safety of the tested chalcones, all the compounds behaved as substrates or inhibitors of at least one cytochrome P450 isoform, as indicated by in silico evaluation. Most compounds lacked tumorigenic, mutagenic, irritant, or reproductive effects, except N3 and N7, as shown by DataWarrior program. The chalcone N9 did not elicit any toxic alteration in doses up to 2000 mg/kg, in female mice. Based on the present results, N9 can be considered a potential candidate for development of a new anti-TB therapeutic choice. / Atualmente, s?o necess?rios novos compostos eficazes para o tratamento da tuberculose (TB). Este estudo analisou a atividade anti-TB de uma s?rie de 16 chalconas derivadas da quinoxalina. A partir de uma triagem inicial in vitro, seis mol?culas, nomeadas N5, N9, N10, N15, N16 e N23 inibiram o crescimento da cepa laboratorial de M. tuberculosis H37Rv. Os tr?s compostos (N9, N15 e N23) com os valores de MIC mais baixos (3.13, 6.25, 5 ?g/mL, respectivamente) foram testados adicionalmente contra isolados cl?nicos e cepas laboratoriais com muta??es nos genes katG ou inhA. A partir deste conjunto experimental, a chalcona quinoxal?nica N9 foi selecionada como composto principal para novas investiga??es. Esta chalcona mostrou um efeito sin?rgico quando combinada com moxifloxacino, de acordo com a avalia??o em ensaio checkerboard. Destaca-se que os efeitos anti-TB de N9 n?o dependeram da inibi??o de ?cidos mic?licos ou da s?ntese de ?cidos graxos n?o hidroxilados, envolvidos em importantes mecanismos de resist?ncia em micobact?rias. Considerando a seguran?a toxicol?gica das chalconas quinoxal?nicas testadas, todos os compostos comportaram-se como substratos ou inibidores de pelo menos uma isoforma do citocromo P450, conforme indicado pela avalia??o in silico. A maioria dos compostos n?o possui efeitos tumorig?nicos, mutag?nicos, irritantes ou reprodutivos, exceto N3 e N7, conforme demonstrado pelo programa DataWarrior. A chalcona quinoxal?nica N9 n?o provocou qualquer altera??o t?xica em doses de at? 2000 mg/kg, em camundongos f?meas. Com base nos resultados atuais, N9 pode ser considerada como potencial candidata para o desenvolvimento de uma nova escolha terap?utica anti-TB.

Made available in DSpace on 2015-04-14T14:51:05Z (GMT). No. of bitstreams: 1 430842.pdf: 2935464 bytes, checksum: 65b5bce8dd872e39bf663fce3ac30b27 (MD5) Previous issue date: 2011-01-27 / A natureza como fonte de inspira??o provou ter grande impacto ben?fico no desenvolvimento de novas metodologias computacionais. Neste cen?rio, an?lises de intera??es entre uma prote?na alvo e um ligante podem ser simuladas por algoritmos inspirados biologicamente (BIA). Neste trabalho, os algoritmos inspirados biologicamente, especialmente algoritmos evolutivos, s?o aplicados a simula??es de docking molecular, que podem ser usadas na busca de novos f?rmacos. Estes algoritmos de docking foram aplicados a sirtu?nas, que comp?em uma importante fam?lia de prote?nas - desacetilases dependentes de NAD - que regulam o silenciamento gen?tico, inibi??o transcricional, estabilidade cromoss?mica, ciclo de divis?o celular e apopt?tico e resposta c?lular a agentes causadores de danos no DNA. Essas prote?nas tem sido alvos moleculares emergentes no desenvolvimento farmac?utico de medicamentos para o tratamento de doen?as humanas. Em fun??o da import?ncia estrutural das prote?nas, neste trabalho foi realizada a modelagem por homologia molecular de SIRT1 humana, utilizando-se a estrutura cristalogr?fica de Sir2 de Thermotoga maritima como modelo. Al?m disso, foi aplicado o procedimento de virtual screening para a SIRT1 modelada contra duas bases de dados. Uma foi baseada em estruturas derivadas da nicotinamida e outra composta por mol?culas da Sigma-Aldrich. Com base nos resultados obtidos no virtual screening, foram utilizados os acoplamentos com valores mais baixos de energia livre de liga??o (Plant Score) para a sele??o das melhores mol?culas. Foi empregada a Similarity Ensemble Approach Tool (SEA), uma abordagem estrat?gica para analisar as rela??es entre as estruturas e a atividade farmacol?gica. Os resultados indicam que algumas mol?culas apresentaram alta afinidade com a SIRT1, sugerindo novos inibidores de SIRT1, e essas mol?culas mostram um elevado n?mero de refer?ncias de atividades farmacol?gicas. Nossos resultados sugerem novos compostos inibidores de SIRT1 que apresentam potencial aplica??o terap?utica

Submitted by Setor de Tratamento da Informa??o - BC/PUCRS (tede2@pucrs.br) on 2015-06-09T11:33:18Z No. of bitstreams: 1 470158 - Texto Completo.pdf: 900834 bytes, checksum: c9822e05947627069fb5b4fc9d1f6005 (MD5) / Made available in DSpace on 2015-06-09T11:33:18Z (GMT). No. of bitstreams: 1 470158 - Texto Completo.pdf: 900834 bytes, checksum: c9822e05947627069fb5b4fc9d1f6005 (MD5) Previous issue date: 2015-03-17 / The international market for essential oils has an annual turnover of 1.8 billion dollars, yet the Brazilian participation in this market is only 0.1%. The vast biodiversity found in Brazil, although still little explored in relation to the chemical composition of its flora, places the country in a very promising position in terms of increasing its future participation in the essential oils market. Basil (Ocimum basilicum L.) is a widely cultivated aromatic plant due to its medicinal properties. The importance of this species lies in the plant architecture, coloration and morphology of its leaves and flowers, in addition to the chemical composition of its essentials oils, giving specific aromas and having various uses in the culinary, perfume and pharmaceuticals industries. In this study, two experiments were performed with the aim of studying germination in simulated hypergravity and open-air cultivation, to evaluate the growth of the basil, its yield and essential oil composition. The extraction of the essential oils was carried out by steam distillation in a Clevenger apparatus. Quantitative and qualitative evaluation of the compounds was performed by gas chromatography coupled to a mass spectrometer detector (GC/MS). The mean values for germination under the effect of hypergravity simulation in protocols 1, 2 and 3 ranged from 81% to 87%. After this stage, the seeds exposed to simulated hypergravity were cultivated in the open-air and the fresh basil leaves were collected after 90 days to obtain the essential oils. The overall yield of oil was 0.2mL to 0.3mL and the essential oil was 0.3% to 0.4%. The largest and most predominant compound in this research was eugenol, ranging from 46% to 62%, with the second largest being linalool, which ranged from 22% to 28%. Further research in this area is essential to understand the real impact of simulated hypergravity on basil, and its effect on auxins and gene expression. / O mercado internacional de ?leos essenciais movimenta anualmente 1,8 bilh?es de d?lares e a participa??o brasileira nesse mercado ? de apenas 0,1%. A grande biodiversidade brasileira, ainda pouco explorada em rela??o ? composi??o qu?mica de sua flora, coloca o Brasil numa situa??o muito promissora para aumentar sua participa??o futura no mercado de ?leos essenciais. O manjeric?o (Ocimum basilicum L.) ? uma planta arom?tica largamente cultivada, devido ? suas propriedades medicinais. A import?ncia dessa esp?cie est? na arquitetura da planta, na colora??o e na morfologia das folhas e flores, al?m da composi??o qu?mica de seus ?leos essenciais, originando aromas espec?ficos e tendo utiliza??o variada na gastronomia, perfumaria e ind?stria farmac?utica. Nesse trabalho, foram realizados dois experimentos, com o objetivo de estudar a germina??o por hipergravidade simulada e o cultivo a c?u aberto para avaliar o crescimento do manjeric?o, rendimento e a composi??o do ?leo essencial. A extra??o do ?leo essencial foi feita por arraste a vapor em aparelho Clevenger. A avalia??o quantitativa e qualitativa dos compostos foi realizada por cromatografia gasosa acoplada a um detector de massas (CG/MS). As m?dias de germina??o deste trabalho foram de 81% a 87%. Ap?s essa etapa, as sementes sob efeito de hipergravidade simulada foram cultivadas a c?u aberto e, depois de 90 dias, foram coletadas folhas frescas de manjeric?o para obter ?leos essenciais. O rendimento total de ?leo foi de 0,2 mL a 0,3 mL e de ?leo essencial de 0,3%. a 0,4%. O composto majorit?rio e predominante em nossas pesquisas foi o eugenol, variando entre 46% a 62%, e o segundo maior composto foi o linalol, que ficou entre 22% a 28%. Pesquisas nessa ?rea s?o essenciais para entender o real impacto da hipergravidade simulada no manjeric?o, seu efeito na auxina e sua express?o g?nica.

Submitted by Setor de Tratamento da Informa??o - BC/PUCRS (tede2@pucrs.br) on 2015-06-11T19:45:55Z No. of bitstreams: 1 470271 - Texto Completo.pdf: 601264 bytes, checksum: 631a8bec7a15cd2f97fae4e0bb07768a (MD5) / Made available in DSpace on 2015-06-11T19:45:55Z (GMT). No. of bitstreams: 1 470271 - Texto Completo.pdf: 601264 bytes, checksum: 631a8bec7a15cd2f97fae4e0bb07768a (MD5) Previous issue date: 2015-03-24 / The esophageal and oral tumors are classified as the most frequent malignancies in Brazil. Esophageal cancer is the eighth most common in the world and oral cancer is ranked as the 5th among malignant neoplasms affecting man in Brazil. The lipopolysaccharide (LPS) are characteristic compounds of the cell wall of gram-negative bacteria. They are able to regulate gene expression of pro-inflammatory cytokines by binding to toll-like receptor 4 (TLR4) via NF-kB pathway. Recent studies show that LPS can increase the migration ability of cell lines of human esophageal cancer HKESC-2 by increasing its binding properties. In the meantime, it has not been tested the effect of LPS on esophageal cancer cells OE19 and OE21 and human oral carcinoma HN30. Thus, this study aimed to determine the action of LPS compounds on the proliferation and viability of cell lines of human esophageal cancer and human oral carcinoma HN30. Were used as treatment LPS for OE19 and OE21 cell lines and the PgLPS (lipopolysaccharide of Porphyromonas gingivalis) for HN30 cell line. Cell viability was assessed using the MTT assay and cell counting. The TLR4 expression by real-time PCR was also evaluated. LPS at higher concentrations decreased significantly cell viability in both cell lines, adenocarcinoma (OE19) and squamous esophageal carcinoma (OE21) at different times of treatment. In addition, both cell lines, OE19 and OE21, expressed TLR4 receptor. Taken together, our data demonstrated that LPS at high concentrations might contribute to tumor death, in agreement with previously data. / Os tumores de es?fago e de boca est?o classificados como as neoplasias malignas mais frequentes no Brasil. O c?ncer de es?fago ? o oitavo mais comum no mundo e o c?ncer de boca ? classificado como o 5? dentre as neoplasias malignas que afetam o homem no Brasil. Os lipopolissac?ridos (LPS) s?o compostos caracter?sticos da parede celular de bact?rias gram-negativas. Eles s?o capazes de regular a express?o de genes de citocinas pr?-inflamat?rias, atrav?s da liga??o ao receptor toll-like 4 (TLR4) via NF-kB. Estudos recentes mostram que o LPS pode aumentar a habilidade de migra??o de linhagens c?lulares de c?ncer de es?fago humano HKESC-2 atrav?s do aumento de suas propriedades de ades?o. Entretanto, ainda n?o foi testado o efeito do LPS sobre as c?lulas de c?ncer de es?fago e de carcinoma oral humano HN30. Deste modo, este estudo teve como objetivo determinar a a??o dos compostos de LPS (derivado de bact?rias) sobre a prolifera??o e viabilidade de linhagens celulares de c?ncer de es?fago humano, e de carcinoma oral humano. Foram utilizados como tratamento o LPS para as linhagens OE19 e OE21 e o PgLPS (lipopolissacar?deo da Porphyromonas gingivalis) para a linhagem HN30. A viabiliadade celular foi avaliada utilizando o ensaio MTT e contagem celular. Tamb?m foi avaliada a express?o do receptor TLR4 por PCR em tempo real. LPS em concentra??es mais elevadas reduziu significativamente a viabilidade celular em ambas as linhagens celulares de c?ncer de es?fago, o adenocarcinoma (OE19) e o carcinoma de c?lulas escamosas (OE21) em diferentes tempos de tratamento. Al?m disso, ambas as linhagens celulares, OE19 e OE21, expressaram o receptor TLR4. Avaliados em conjunto, os nossos dados demonstram que o LPS em concentra??es elevadas pode contribuir para a morte tumoral, de acordo com dados pr?vios.

Submitted by Setor de Tratamento da Informa??o - BC/PUCRS (tede2@pucrs.br) on 2015-06-25T11:34:05Z No. of bitstreams: 1 471145 - Texto Completo.pdf: 583122 bytes, checksum: b9760b9161356a851110fa2f73635187 (MD5) / Made available in DSpace on 2015-06-25T11:34:05Z (GMT). No. of bitstreams: 1 471145 - Texto Completo.pdf: 583122 bytes, checksum: b9760b9161356a851110fa2f73635187 (MD5) Previous issue date: 2015-03-09 / Glioblastoma multiform (GBM) is a highly aggressive tumor of the central nervous system and has a few available therapies. In GBM, proinflammatory signaling pathways, such as STAT3 and NF- ?B are aberrantly activated and associated with cell proliferation, survival, invasion and resistance to chemotherapy. Therefore, inhibition of these pro-inflammatory pathways has been suggested as a strategy to combat malignant cells. Resolvins of D-series promote resolution of inflammation by decreasing the activation of NF-?B. The Resolvin D2 (RvD2) is derived from a double sequence of docosahexaenoic acid lipoxygenation, which is derived from the essential fatty acid Omega-3. Our hypothesis is that the resolvins, by direct or indirect inhibition of pro-inflammatory pathways, could compromise the survival and growth of glioma. Our goal is to assess the role of RvD2 and its precursor 17 (R) HDHA (HR17) on tumor cell proliferation and survival in murine glioma model. For this, murine glioma cell line (GL261) was treated in vitro with RvD2 and HR17, and cell death and proliferation were evaluated. Furthermore, the effect of RvD2 and HR17 was evaluated in vivo after GL261 brain implantation; histopathological characteristics and immunohistochemistry for activated caspase-3 were evaluated to. It was found that RvD2 GL261 induces apoptosis in vitro. Furthermore, in vivo treatment of RvD2 and HR17 increased the number of tumor cells positive for activated caspase-3, although not alter tumor area. Interestingly, the HR17 treatment reduces tumor mitotic index in vivo. These results suggest that RvD2 and HR17 have a potential role in the induction of apoptosis in murine glioma cells. / Glioblastoma multiforme (GBM) ? um tumor altamente agressivo do Sistema Nervoso Central e possui poucas terapias dispon?veis. Em GBM, vias de sinaliza??o pr?-inflamat?rias, como da STAT3 e NF-?B, s?o aberrantemente ativadas e associadas com a prolifera??o celular, sobreviv?ncia, invas?o e resist?ncia ? quimioterapia. Por conseguinte, a inibi??o dessas vias pr?inflamat?rias tem sido sugerida como uma estrat?gia para combater as c?lulas malignas. As resolvinas da s?rie D promovem resolu??o da inflama??o diminuindo a ativa??o de NF-?B. A Resolvina D2 (RvD2) deriva de uma sequencia de dupla lipoxigena??o do ?cido docosahexaen?ico, o qual ? derivado do ?cido graxo essencial Omega-3. Nossa hip?tese ? que as resolvinas, por inibi??o direta ou indireta de vias pr?-inflamat?rias, poderiam comprometer a sobreviv?ncia e o crescimento do glioma. Nosso objetivo consiste em avaliar o papel da RvD2 e de seu precursor 17(R)HDHA (HR17) sobre a prolifera??o de c?lulas tumorais e sobreviv?ncia em um modelo de glioma murino. Para isso, a linhagem de c?lulas de glioma murino (GL261) foi tratada in vitro com RvD2 e HR17, e amorte celular e prolifera??o foram avaliadas. Al?m disso, o efeito de RvD2 e HR17 foi avaliado in vivo ap?s o implante de GL261 no c?rebro, avaliando-se caracter?sticas histopatol?gicas e a imunohistoqu?mica para caspase-3 ativada. Verificou-se que RvD2 induz apoptose de GL261 in vitro. Al?m disso, o tratamento de RvD2 e HR17 in vivo aumentou o n?mero de c?lulas tumorais positivas para caspase-3 ativada, embora n?o alterassem a ?rea do tumor. Curiosamente, o tratamento HR17 reduz o ?ndice mit?tico tumoral in vivo. Estes resultados sugerem que RvD2 e HR17 t?m um potencial papel na indu??o de apoptose em c?lulas de glioma murino.